Pharmacological and computational evaluation of an isoxazolone derivative for mitigating cisplatin-induced neuropathic pain

Abstract

Cisplatin-induced neuropathic pain poses a significant clinical challenge. This study induced neuropathy via cisplatin treatment, measuring pain levels through mechanical threshold and thermal escape latency. Isoxazolone derivatives were administered at doses of 20, 40, and 60 mg/kg to evaluate their effects on allodynia and pregabalin, a known therapeutic agent, was used for comparison. Place preference tests were conducted to gauge responses, while molecular docking and dynamic simulations assessed the binding affinity for relevant receptors. Results showed that cisplatin-induced neuropathy by day four, with reduced mechanical threshold and sustained thermal escape latency for eight days. Isoxazolone derivatives at 20 mg/kg and 40 mg/kg effectively reversed allodynia, while 60 mg/kg showed limited impact. Pregabalin exhibited similar effects, though less significance after day 10. Place preference tests demonstrated positive responses to both isoxazolone derivatives and pregabalin in allodynic rats. Molecular docking analysis highlighted strong binding to receptors, particularly cyclooxygenase-2 (Cox-2), Tumor Necrosis Factor (TNF)-α. Binding free energies indicated potent inhibitory activity of isoxazolone derivatives against Cox-2 and TNF-α. This study underscores the potential of isoxazolone derivatives as therapeutic agents for cisplatin-induced mechanical allodynia, with innovative implication for neuropathic pain treatment. Further research and validation are necessary to confirm their therapeutic efficacy and safety for human clinical use.

Keywords

• Cisplatin
• Neuropathic pain
• TNF-α
• Isoxazolone derivatives
• Animal models
• Computational study